Decoding Nanomaterial-Biosystem Interactions through Machine Learning.

The interactions between biosystems and nanomaterials regulate most of their theranostic and nanomedicine applications. These nanomaterial-biosystem interactions are highly complex and influenced by a number of entangled factors, including but not limited to the physicochemical features of nanomaterials, the types and characteristics of the interacting biosystems, and the properties of the surrounding microenvironments. Over the years, different experimental approaches coupled with computational modeling have revealed important insights into these interactions, although many outstanding questions remain unanswered. The emergence of machine learning has provided a timely and unique opportunity to revisit nanomaterial-biosystem interactions and to further push the boundary of this field. This minireview highlights the development and use of machine learning to decode nanomaterial-biosystem interactions and provides our perspectives on the current challenges and potential opportunities in this field.

SIRT 1 Activator Loaded Inhaled Antiangiogenic Liposomal Formulation Development for Pulmonary Hypertension.

Pulmonary hypertension (PH) is characterized by the rise in mean pulmonary arterial pressure (≥ 20 mmHg at rest) due to the narrowing of the pulmonary arterial networks. Current treatments provide symptomatic treatment and the underlying progress of PH continues leading to higher mortality rates due to non-reversal of the disease. This warrants the need for drug therapies targeting angiogenesis and vascular remodeling mechanisms. Resveratrol, SIRT 1 activator, alters various signaling pathways, inhibits apoptosis, and negatively regulates angiogenesis either by increasing the production of anti-angiogenic factors or inhibiting pro-angiogenic factors. Our work describes the liposomal formulation development, physicochemical characterization, and in vitro aerosolization performance of resveratrol liposomal dry powder formulation. The resveratrol liposomal dry powder formulation reduces the right ventricular systolic pressure measured during right jugular vein catheterization and significantly reverses the PH disease pathological changes as demonstrated by histological observations of pulmonary arterial lumen and ventricular hypertrophy. The developed resveratrol liposomal dry powder formulation alleviates the pulmonary arterial remodeling through its antiangiogenic mechanism and indicates a promising therapeutic strategy for PH treatment.

Microneedles for transdermal drug delivery: a systematic review.

Transdermal route has been explored for various agents due to its advantage of bypassing the first pass effect and sustained release of drug. Due to strong barrier properties of the skin, mainly stratum corneum (SC), the delivery of many therapeutic agents across the skin has become challenging. Few drugs with specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be effectively administered via transdermal route. However, delivery of hydrophilic drugs and macromolecular agents including peptides, DNA and small interfering RNA is challenging. Drug penetration through the SC may involve bypass or reversible disruption of SC layer by various means. Recently, the use of micron-scale needles has been proposed in increasing skin permeability and shown to dramatically increase permeation, especially for macromolecules. Microneedles (MNs) can penetrate through the SC layer of the skin into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. This review summarizes the types of MNs and fabrication techniques of different types of MNs. The safety aspects of the materials used for fabrication have been discussed in detail. Biological applications and relevant phase III clinical trials are also highlighted.

Transmucosal Nanoparticles: Toxicological Overview.

Nanoparticles have specific physicochemical properties different to bulk materials of the same composition and such properties make them very attractive for commercial and medical applications. Mucoadhesive nanoparticulate dosage forms are designed to enable prolonged retention of these nanoparticles at the site of application, providing a controlled drug release for improved therapeutic outcome. Moreover, drug delivery across the mucosa bypasses the first-pass hepatic metabolism and avoids the degradation by gastrointestinal enzymes. However, like most new technologies, there is a rising debate concerning the possible transmucosal side effects resulting from the use of particles at the nano level. In fact, these nanoparticles on entering the body, deposit in several organs and may cause adverse biological reactions by modifying the physiochemical properties of living matter. Several investigators have found nanoparticles responsible for toxicity in different organs. In addition, the toxicity of nanoparticles also depends on whether they are persistent or cleared from the different organs of entry and whether the host can raise an effective response to sequester or dispose of the particles. In contrast to many efforts aimed at exploiting desirable properties of nanoparticles for medicine, there are limited attempts to evaluate potentially undesirable effects of these particles when administered intentionally for medical purposes. This chapter focuses on the overview of the mucosal systems, fate of nanoparticles, mechanism of nanoparticle's toxicity and the various toxicity issues associated with nanoparticles through mucosal routes.

Design, development, and technical considerations for dry powder inhaler devices.

The dry powder inhaler (DPI) stands out as a highly patient-friendly and effective pulmonary formulation, surpassing traditional and other pulmonary dosage forms in certain disease conditions. The development of DPI products, however, presents more complexities than that of other dosage forms, particularly in device design and the integration of the drug formulation. This review focuses on the capabilities of DPI devices in pulmonary drug delivery, with a special emphasis on device design and formulation development. It also discusses into the principles of deep lung particle deposition and device engineering, and provides a current overview of the market for DPI devices. Furthermore, the review highlights the use of computational fluid dynamics (CFD) in DPI product design and discusses the regulatory environment surrounding these devices.

Oral Self-Nanoemulsifying System Containing Ionic Liquid of BX795 Is Effective against Genital HSV-2 Infection in Mice.

BX795 is an emerging drug candidate that has shown a lot of promise as a next-generation non-nucleoside antiviral agent for the topical treatment of herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) infections. Our studies indicated that BX795 has limited oral bioavailability, which could be attributed to its low and pH-dependent solubility. Lipid-based formulations such as self-nanoemulsifying systems (SNESs) can improve the solubility and oral bioavailability of BX795, but the poor lipid solubility of BX795 further limits the development of SNES. To improve the loading of BX795 into SNES, we evaluated the ability of various bulky and biocompatible anions to transform BX795 into an ionic liquid (IL) with higher lipid solubility. Our studies showed that sodium lauryl sulfate and docusate sodium were able to transform BX795 into IL. Compared to pure BX795, the developed BX795 ILs showed differential in vitro cytocompatibility to HeLa cells but exhibited similar in vitro antiviral activity against HSV-2. Interestingly, BX795 docusate (BX795-Doc), an IL of BX795 with ∼135-fold higher lipid solubility than pure BX795, could be successfully incorporated into an SNES, and the developed BX795-Doc-SNES could readily form nanoemulsions of size ≤200 nm irrespective of the pH of the buffer used for dilution. Our in vitro studies showed that BX795-Doc-SNES retained the inherent antiviral activity against HSV-2 and showed similar in vitro cytocompatibility, indicating the availability of BX795 from the SNES in vitro. Finally, orally delivered SNES containing BX795-Doc showed a significant reduction in HSV-2 infection in mice compared to the untreated control. Thus, the transformation of BX795 into IL and the subsequent incorporation of the BX795 IL into the SNES are an effective strategy to improve oral therapy of genital herpes infection.

Current status of mannose receptor-targeted drug delivery for improved anti-HIV therapy.

In the pursuit of achieving better therapeutic outcomes in the treatment of HIV, innovative drug delivery strategies have been extensively explored. Mannose receptors, which are primarily found on macrophages and dendritic cells, offer promising targets for drug delivery due to their involvement in HIV pathogenesis. This review article comprehensively evaluates recent drug delivery system advancements targeting the mannose receptor. We have systematically described recent developments in creating and utilizing drug delivery platforms, including nanoparticles, liposomes, micelles, noisomes, dendrimers, and other nanocarrier systems targeted at the mannose receptor. These strategies aim to enhance drug delivery specificity, bioavailability, and therapeutic efficacy while decreasing off-target effects and systemic toxicity. Furthermore, the article delves into how mannose receptors and HIV interact, highlighting the potential for exploiting this interaction to enhance drug delivery to infected cells. The review covers essential topics, such as the rational design of nanocarriers for mannose receptor recognition, the impact of physicochemical properties on drug delivery performance, and how targeted delivery affects the pharmacokinetics and pharmacodynamics of anti-HIV agents. The challenges of these novel strategies, including immunogenicity, stability, and scalability, and future research directions in this rapidly growing area are discussed. The knowledge synthesis presented in this review underscores the potential of mannose receptor-based targeted drug delivery as a promising avenue for advancing HIV treatment. By leveraging the unique properties of mannose receptors, researchers can design drug delivery systems that cater to individual needs, overcome existing limitations, and create more effective and patient-friendly treatments in the ongoing fight against HIV/AIDS.

Safe Subunit Green Vaccines Confer Robust Immunity and Protection against Mucosal Brucella Infection in Mice.

Brucellosis is a zoonotic disease that causes significant negative impacts on the animal industry and affects over half a million people worldwide every year. The limited safety and efficacy of current animal brucellosis vaccines, combined with the lack of a licensed human brucellosis vaccine, have led researchers to search for new vaccine strategies to combat the disease. To this end, the present research aimed to evaluate the safety and efficacy of a green vaccine candidate that combines Brucella abortus S19 smooth lipopolysaccharide (sLPS) with Quillaja saponin (QS) or QS-Xyloglucan mix (QS-X) against mucosal brucellosis in BALB/C mice. The results of the study indicate that administering two doses of either sLPS-QS or sLPS-QS-X was safe for the animals, triggered a robust immune response, and enhanced protection following intranasal challenge with S19. Specifically, the vaccine combinations led to the secretion of IgA and IgG1 in the BALF of the immunized mice. We also found a mixed IgG1/IgG2a systemic response indicating evidence of both Th1 and Th2 activation, with a predominance of the IgG1 over the IgG2a. These candidates resulted in significant reductions in the bioburden of lung, liver, and spleen tissue compared to the PBS control group. The sLPS-QS vaccination had conferred the greatest protection, with a 130-fold reduction in Brucella burdens in lung and a 55.74-fold reduction in the spleen compared to PBS controls. Vaccination with sLPS-QS-X resulted in the highest reduction in splenic Brucella loads, with a 364.6-fold decrease in bacterial titer compared to non-vaccinated animals. The study suggests that the tested vaccine candidates are safe and effective in increasing the animals' ability to respond to brucellosis via mucosal challenge. It also supports the use of the S19 challenge strain as a safe and cost-effective method for testing Brucella vaccine candidates under BSL-2 containment conditions.

Comprehensive review on novel targets and emerging therapeutic modalities for pulmonary arterial Hypertension.

Pulmonary Arterial Hypertension (PAH) is the progressive increase in mean pulmonary arterial pressure (mPAP) (≥20 mmHg at rest). Current treatment strategies include the drugs targeting at nitric oxide pathway, endothelin receptors, prostaglandin receptors, thromboxane receptors and phosphodiesterase inhibitors, which provides the symptomatic relief. Despite of these treatments, the mortality amongst the PAH patients remains high due to non-reversal of the condition. This review primarily covers the introduction of PAH and the current treatments of the disease. This is followed by the newer disease targets expressed in the pathobiology of the disease like Rho Kinase Pathway, Vasoactive Intestinal Peptide Pathway, Receptor Tyrosine Kinases, Serotonin signalling pathway, Voltage-gated potassium (Kv) channel pathway. Newer formulation strategies for targeting at these specific receptors were covered and includes nano formulations like liposomes, Micelles, Polymeric Nanoparticles, Solid Lipid Nanoparticles (SLN), Bioresorbable stents, NONOates, Cell-Based Therapies, miRNA therapy for PAH. Novel targets were identified for their role in the pathogenesis of the PAH and needs to be targeted with new molecules or existing molecules effectively. Nanosystems have shown their potential as alternative carriers on the virtue of their better performance than traditional drug delivery systems.

A triple combination 'nano' dry powder inhaler for tuberculosis: in vitro and in vivo pulmonary characterization.

Inhalation route of drug delivery is the most favorable for pulmonary infections wherein direct drug delivery is desired to the lungs. Tuberculosis is one such infection suffering from poor therapeutic efficacy because of low patient compliance due to high drug dosing and lengthy treatment protocols. The current research work was undertaken to develop a dry powder inhaler (DPI) for administration of three first-line antitubercular antibiotics directly to the lungs to improve the treatment rates. Nanoformulations of isoniazid, pyrazinamide, and rifampicin were prepared, spray-dried to obtain a dry powder system, and blended with inhalation grade lactose to develop the DPI. The DPI was evaluated for its flow properties, pulmonary deposition, dissolution profile, and stability. The DPI possessed excellent flow properties with a fine particle fraction of 45% and a mass median aerodynamic diameter of approximately 5 µm indicating satisfactory lung deposition. In vitro drug release exhibited a sustained release of the formulations. In vivo studies showed a prolonged deposition in the lung at elevated concentrations compared to oral therapy. Stability studies proved that the formulation remained stable at accelerated and long-term stability conditions. The DPI could complement the existing oral therapy in enhancing the therapeutic efficacy in patients.

Xyloglucan based mucosal nanovaccine for immunological protection against brucellosis developed by supercritical fluid technology.

Vaccines delivered via the mucosal route have logistic benefits over parenteral or intramuscular vaccines as they offer patient compliance. This study presents the first intranasal, controlled release, subunit nanovaccine comprising mucoadhesive tamarind seed polymer (xyloglucan) based nanoparticles produced using an efficient, environmentally compatible, and industrially scalable technique: rapid expansion of supercritical solution. The nanovaccine formulation aimed against brucellosis comprised xyloglucan nanoparticles loaded separately with antigenic acellular lipopolysaccharides from B. abortus (S19) and the immunoadjuvant quillaja saponin. The nanovaccine elicited prolonged humoral and cell-mediated immunity in female Balb/c mice. Nasal vaccination with the nanovaccine resulted in higher levels of mucosal IgA and IgG than with an aqueous solution of soluble lipopolysaccharides and quillaja saponin. Systemic immunity triggered by the nanovaccine was evidenced by higher IgG levels in sera post priming and boosting. The nanovaccine induced a mixed Th1/Th2 type of immunity with higher IgG2a levels and thus a polarized Th1 response. The results suggest that the nanovaccine administered by homologous nasal route can prime the immune system via the mucosal and systemic pathways and is a good candidate for vaccine delivery.

Development of anti-angiogenic erlotinib liposomal formulation for pulmonary hypertension: a QbD approach.

Pulmonary arterial hypertension (PAH) is the increase in mean pulmonary arterial pressure (> 25 mmHg). The development of the non-reversible plexiform lesions on the arterial walls of the pulmonary arteries has evolved as the reason to increase the pressure. The current treatments are directed towards the vasodilation of the pulmonary arteries via the endothelin, prostacyclin, and NO pathways which provides symptomatic relief. Deeper understanding of the disease leads to the various pathophysiological targets that play an important role in the development of PAH. Out of these, the angiogenetic mechanism of the pulmonary arterial smooth muscle cells has been proved to play an important role in PAH. Targeted therapies by anti-proliferative drugs may lead to the efficient treatment strategies to the root cause of PAH. Erlotinib, a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR), has shown promising results in clinical trials of PAH. The objective of the work has been the development of liposomal formulation of anti-proliferative drug, erlotinib HCl, via Quality by Design (QbD) approach. The liposomal formulation was developed using thin-film hydration technique and characterised for various physicochemical parameters, like particle size, % entrapment efficiency, DSC, FTIR, pXRD, and TEM. In the drug release study, the formulation showed sustained release of erlotinib over 24 h in simulated lung fluid pH 7.4. This developed formulation was evaluated in zebrafish tail fin regeneration assay for its anti-angiogenetic activity. The liposomal formulation inhibited the tail fin regeneration for 14 days indicating anti-angiogenetic activity.

Effect of various anticoagulants on the bioanalysis of drugs in rat blood: implication for pharmacokinetic studies of anticancer drugs.

BACKGROUND: Pharmacokinetic studies are vital in development and optimization of drugs. While blood samples can be collected either in EDTA, heparin or citrate containing tubes for the estimation of drug levels in plasma, EDTA tubes are more commonly used. The purpose of this study was to evaluate the effects of anticoagulants on bioanalysis of drugs. Six drugs used extensively in cancer therapy were selected. Albino wistar rats (N = 6 per drug) were dosed with one of the following drugs intraperitoneally-pemetrexed (50 mg/kg), imatinib (50 mg/kg), erlotinib (25 mg/kg), meropenem (60 mg/kg), 6-mercaptopurine (20 mg/kg) and voriconazole (6 mg/kg). Blood samples were collected 2 h after dosing (1 h in 6-mercaptopurine group due to short half-life) by terminal bleeding from the retro-orbital plexus. Blood was collected in each of Disodium ETDA, heparin, trisodium citrate (TSC) and no anticoagulant (plain) tubes. Drug levels in these samples were determined by validated HPLC assays. ANOVA with Tukey's post hoc test was performed to identify statistically significant differences in drug concentrations in anticoagulant tubes. p < 0.05 was considered statistically significant. RESULTS: Significant differences in concentration between anticoagulant tubes was observed in case of erlotinib (p = 0.013) and meropenem (p = 0.00), while borderline statistical significance for pemetrexed (p = 0.076). TSC tubes overestimated erlotinib levels, heparin tubes underestimated meropenem concentrations and EDTA tubes overestimated pemetrexed concentrations. CONCLUSIONS: Careful selection of anti-coagulant is necessary for accurate characterization of pharmacokinetics of drugs. Routine use of EDTA tubes may lead to erroneous interpretation of pharmacokinetic data.

Detoxification of Abrus precatorius L. seeds by Ayurvedic Shodhana process and anti-inflammatory potential of the detoxified extract.

BACKGROUND: Abrus precatorius seeds traditionally used for the treatment of sciatica and alopecia contains the toxic protein, abrin, a Type II Ribosome Inactivating Protein. Ayurveda recommends the use of Abrus seeds after the Shodhana process (detoxification). OBJECTIVE: The current study was aimed at performing the Shodhana process, swedana (boiling) of Abrus precatorius seeds using water as a medium and to evaluate the anti-inflammatory potential of seed extract post detoxification. MATERIALS AND METHODS: Non-detoxified and detoxified extracts were prepared and subsequently subjected to various in vitro and in vivo assays. In hemagglutination assay, the non-detoxified extract shows higher agglutination of RBCs than detoxified extract indicating riddance of toxic hemagglutinating proteins by Shodhana. This was confirmed by the SDSPAGE analysis of detoxified extract revealing the absence of abrin band in detoxified extract when compared to non-detoxified extract. RESULTS: The cytotoxicity assay in HeLa cell line expresses a higher reduction in growth percentage of the cells with non-detoxified extract as compared to detoxified extract indicating successful detoxification. Brine shrimp lethality test indicated the reduction in toxicity index of detoxified extract as compared to non-detoxified extract. Further, the whole body apoptosis assay in zebrafish revealed that percentage of viable cells were greater for detoxified extract than non-detoxified extract. The anti-inflammatory studies using carrageenan induced paw edema model in rats was carried out on the extracts with doses of 100 mg/kg and 200 mg/kg, per oral, where the detoxified extract exhibited significant inhibition of rat paw edema at both the doses comparable to that of Diclofenac sodium. CONCLUSION: Absence of toxicity and the retention of the anti-inflammatory activity of detoxified Abrus seed extract confirmed that the Swedana process is effective in carrying out the detoxification without affecting its therapeutic potential.